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Publication numberUS2779762 A
Publication typeGrant
Publication dateJan 29, 1957
Filing dateOct 9, 1953
Priority dateOct 9, 1953
Publication numberUS 2779762 A, US 2779762A, US-A-2779762, US2779762 A, US2779762A
InventorsRobertson Alice Ota, Link Karl Paul, Dale N Robertson
Original AssigneeWisconsin Alumni Res Found
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
3-substituted-aminomethyl-4-hydroxy-6-substituted-coumarins
US 2779762 A
Abstract  available in
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Description  (OCR text may contain errors)

United States Patent 3-SUBSTITUTED-AMlNOMETHYL-4-HYDROXY-6- SUBSTITUTED-COUMARINS Alice Ota Robertson and Dale N. Robertson, Madison,

and Karl Paul Link, Middleton, Wis., assignors to Wisconsin Alumni Research Foundation, Madison, Wis., a corporation of Wisconsin I No Drawing. Application October 9, 1953, Serial No. 385,299

6 Claims. (Cl. 260247.7)

The present invention relates to chemical compounds and the processes of making the same. More specifically the invention relates to certain 3-substituted-aminomethyl- 4-hydroxy-6-substituted-coumarins. The compounds can be represented by the following general formula:

X cHm where X is selected from the group consisting of halogen, lower alkyl and lower alkoxy groups, R is selected from the group consisting of hydrogen and methyl, R is a lower alkyl group andR and R together with the N form a heterocyclic group.

GENERAL PROCESS To a solution of formaldehyde and the appropriate amine in absolute ethanol at room temperature is first added the appropriate 4-hydroxy-o-substituted-coumarin. The reactants are ordinarily reacted in equimolar quantities although the amine can be employed in excess e. g. 0.25 mole excess. The 4-hydroxy-6-substituted-coumarin can be added to the formaldehyde-amine solution in the dry solid state or in ethanol solution. The reactants are thoroughly mixed and allowed to stand at room temperature until an extensive precipitation has occurred. This may be within a few minutes or overnight or longer. Precipitation may be hastened by cooling or by the addition of absolute ethyl ether or other non-polar solvent. In some cases the warming of the reaction mixture is preferred as a means for speeding up the reaction, although refluxing, for example, should be avoided where the reactants or particular reaction product tends to undergo decomposition at refluxing temperatures. The compounds can be conveniently recovered from the reaction mixtures by filtration. As they are obtained analytically pure, recrystallization is not necessary. Some compounds, however, were found to contain water of crystallization which is not removed by drying in vacuo for 24 hours at room temperature.

The following specific examples will serve to illustrate the invention.

EXAMPLE I 3-ethyl-aminomethyl-4-hydr0xy-6-chl0r0c0umarin To a solution of 0.25 mole of formaldehyde and 0.3 mole of ethylamine in 750 ml. of absolute ethanol is first added 0.25 mole of 4-hydroxy-6-chlorocoumarin. The resulting reaction mixture is next mixed at room temperature and then allowed to stand at about 5 C. in a refrigerator overnight. The desired product which separates as a precipitate is recovered by filtration. It has a melting point of 224-23l C. (d) i. e. with decomposition.

2,779,762 Patented Jan. 29, 1957 ice EXAMPLE II 3-n-butyl-aminomethyl-4-hyroxy-6-chlorocoumarin This product is prepared in accordance with the above described process by employing as the amine, normal butylamine. The desired product has a melting point of l98-222 C. (d).

EXAMPLE III 3-s-butyl-amin0methyl-4-hydr0xy-6-chl0r0coumarin This product is prepared as described above employing as the amine, secondary butylamine. It has a melting point of 232-238" C. (d).

EXAMPLE IV 3- a,u-dimethylethanol) -amz'n0methyl-4-hydroxy-6- chlorocoumarin This product is prepared as described above employing as the amine, 2-amino-Z-methyl-propanol-1. It has a melting point of 205-218 C. (d).

EXAMPLE V I 3-dimethyl-amin0methyl-4-hydr0xy-6-br0m0c0umarin This product is prepared as described above by reacting formaldehyde, dimethylamine and 4-hydroxy-6-bromocoumarin in equimolar quantities. It has a melting point of 186-188 C. (d).

EXAMPLE VI 3-i-butyl-aminomethyl-4-hydr0xy-6-bromocoumarin This product is prepared as described above in Example V, employing as the amine, iso-butylamine. It has a melting point of 205225 C. (d).

EXAMPLE VII 3-methyl-amin0methyl-4-hydroxy-6-methylcoumarin This product is prepared as described above by reacting formaldehyde, methylamine and 4-hydroxy-6-methylcoumarin in equimolar quantities. It has a melting point of 223-23l C. (d).

EXAMPLE VIII 3-benzyl-amin0methyl-4-hydr0xy-6-methylcoumarin This product is prepared as described above in Example VII, employing as the amine, benzylamine. It has a melting point of l25-126 C. (d).

184-185 C. (d). A similar type N-heterocycloalkyl product can be prepared by using tetrahydropyrrole as the amine.

EXAMPLE X 3-carbethoxy-methyl-aminomethyl-4-hydroxy-6-methylcoumarin This product is prepared as described above employing ethyl glycinate as the amine. It has a melting point of 263-264 C. (d).

EXAMPLE XI 3-carbethoxy-ethyl-aminomethyl-4-hydroxy-6-methylcoumarin This product is prepared as described above employing ethyl u-alaninate as the amine. It has a melting point of 282 C. (d). In this example and Example X, other lower alkyl (methyl, propyl, etc.) esters of the amino acids can be employed to prepare the desired carbalkoxy derivatives.

EXAMPLE XII 3-n-pr0pyl-amin0methyl-4-lzydroxy-6-methoxyc0umarin This product is prepared as described above by reacting formaldehyde, :normal propylamine and 4-hydroxy-6- methoxycoumarin. It has a melting point of 163-164 C. .(d). (The.entire sample on melting became a mass of bubbles, but a clear liquid did not result.)

EXAMPLE XIII 3-n-hexyl aminomethyl14-hydroaqyefi-methoxycoumarzn This product is prepared as described above in Example XII, employing as the amine, normal hexylamine. It-has a melting point of 132-136 C EXAMPLE XIV 3-phenylethyl-amin0methyl-4-hydr0xy- -6-meth0xyc0umarin This product is prepared as described above employing as the amine, pllenylethylamine. It has a melting point of 146-147 C.

EXAMPLE XV This product is prepared as described above employing as the amine, l-amino-propanol-Z. It has a melting point of 246 C. (d).

EXAMPLE XVI 3 -i-prpyl-ami 210methyl-4-hydl 0xy-6-ethoxycoumarin This product is prepared as described above by reacting formaldehyde, iso-propylamine and 4-hydroXy-6-ethoxycoumarin. It has a melting point of 140-143 C. (d).

EXAMPLE XVII '3-cyc]0hexyl-aminomethyZ-4-hydroxy-6-eth0xyc0umarin This product is prepared as described above in Example XVI by employing as theamine, cyclohexylamine. It has a melting point of 145-l50 C. (d).

EXAMPLE XVIII 3 -al lyl-aminometh yl-4-hydroxy-6 -el hoxycoumarflz This product is prepared as described above employing as the amine, allylamine. It has a melting point of 228-234 C. (d).

Additional compounds prepared as described above are set forth in the following tables.

TABLE I 3-substituted-amin0methyl-4-hydroxy-6-chlorocoumarins Melting Amine Dis- 3-Substituent Point, 0. closed in Example CH N(GH3)2 197 V -CHgNHCsH1-I1 215-220 ((1) XII -CHQNHC3H7'I 230-2 ((1) XVI -CH NHC H\3-n 159-160 XIII CH2NH cyclohexyl 202 (d) XVII -CH NH(CH2)zCt-,H 185-225 ((1) XIV -Piperidinometllyl 184-185 ((1) IX OHQNHOH2OH: OH2 298-300 ((1) XVIII CHQNEGHQCI}HGHB 190-209 ((1) XV .4 TABLE 11 3-substituted-aminomethyl-4-hydr0xy-6-brom0c0umarins Melting Amine Dis- 3-Substituent "Point, 0. closed in Example CH NHC2H5 217-225 I 'CH NHG3H1-n 220-230 XII --GH NHC4H7-1 237-242 XVI .-.oH ;NHclHt-n 218-229 11 OB2NHC4HD-S 2401248 III -CHNHCeHia-n 1 163. 5-165 XIII -CHzNH cyclohexyl 199-213 XVII CHzNH(CH2)2CeH5 192-227 XIV .O zN iOHi0H=OH2 197-244 XVIII -OH NHCH?HCHs 202 XV on r oH,NH(|3-on,on 224-230 Iv 1 Resolidifies and is finally molten again by 194 0. 2 Resolidifies and is finally molten again by 212 C. 3 All compounds melt with decomposition.

TABLE III 3-substituIed-amin0methyl-4-hydr0xy-6-methylcoumarins Melting Point, Amine 3-Substituent C. Disclosed in Example CH N(OHa)z 189 (d) V CH NHC H 1 171 (d) I CHzNHQgH'J-Il 148-150 ((1) XII -CH2NHC3H -i 166 (d) XVI OH NHO4Hn-n 128-132 ((1) II OH NHG H -i 165 ((1) VI OB NHC4Ha-s 142 ((1) III OH NHc Hw-n 138 XIII OH NH eyclohexyl 186-187 ((1) XVII CHZNH(CH2)2CQH5 2 -140 X'IV --OH NHCH;CH=CH1 294-295 ((1) XVIII -CH NHOH (|]HOH 197. 5-201 ((1) XV OH i -CH NHC-OH2OH 181-184 IV 1 When heated slowly slnters at 171 0. and gradually melts up to 218 vO. If introduced in the bath at 171 C. the compound decomposes vigprously, resolidifles and melts again, with decomposition, at 215- 2 1 Resolidifies and melts again at 183-185 0.

TABLE IV 3-substituted-amin0meIhyl-4-hydr0xy- 6-metlzoxycoumarins Amine 3-Substituent Metling Disclosed Point,-C. in Example -CHNHOH3 247-25 ((1) VII CH N(CHa)2 198 ((1) V CH NHO H 1 108-188 ((1) I -CH NHCaH7-i 164 (d) XVI OH' NHClH -n 163-164 (d) II -OH NHC H -i I 183-250 (d) VI CHZNH cyclohexyl -166 (d) XVII -OH;NHOH G H 3 126-128 VIII -CH NHGHZCH=CH 249-252 (11) XVIII -Piperidinomethyl 178 IX introduced in bath at188 C 2 Decomposed over entire range after sintering at 165 C. a Entire sample became a mass of bubbles with no resulting clear liquid.

\ Decomposes gradually over entire range. Deoomposes vigorously if TABLE V 3-substituted-amin0methyl-4-hydr0xy-6-ethoxycoumarins Amine 3-Substltuent Melting Disclosed Point, C. in Example CH=N(CH 200 (d) V -CH2NHC7H5 158-160 ((1) I -CH NHCaII1-n 156-160 ((1) XII -CHrNHO H;-n 160 II -CH NHC4Hs-S 140442 (d) III -CHzNHCH2CaH5 133-135 VIII CH;NH (CH2)2C|1H5 1 144-145 (d) XIV CH NHCH1GllEIOHz 178 (d) XV -Plperldinomethyl 162 (d) IX 1 Decomposed after sintering at 115 C.

In the tables and description (d) denotes decomposition. The compounds melting over a wide range usually darken and sinter several degrees below the melting range.

In the above examples it will be understood that X represents any of the halogens such as iodine and fluorine as well as the chlorine and bromine derivatives, and that X represents various other lower alkyl and lower alkoxy groups such as ethyl, propyl, butyl, amyl, hexyl, propoxy, butoxy, etc. It will also be understood that R represents substituted lower alkyl groups such as disclosed in Examples IV, VIII, X, XI, XIV, and XV, as well as cycloalkyl and unsaturated alkyl groups such as disclosed in Examples XVII and XVIII. The compounds of the invention are of interest in various fields including the 4-hydroxycoumarin anticoagulant field.

The various names to be applied to the compounds listed in the above tables will be obvious. In Table I, for example, the first compound is 3-dimethyl-aminomethyl-4-hydroxy-6-chlorocoumarin and the seventh compound is 3-piperidinomethyl-4-hydroxy-6-chlorocoumarin. Similarly, the seventh compound in Table IV is 3-cyclohexyl-aminornethyl-4-hydroxy-6-methoxycoumarin. Mixed amines, e. g. methyl, ethyl-amine, can also be employed to prepare various compounds where R is methyl and R is a lower alkyl group. Other compounds falling within the scope of the invention are listed in the The fifth or last compound in this table is 3-morpholinomethyl-4-hydroxy-6-ethoxycoumarin and is prepared by reacting formaldehyde, morpholine and 4-hydroxy-6- ethoxycoumarin in equimolar quantities in accordance with the above examples. The other 3-morpholino compounds are prepared in a like manner employing morpholino as the amine and by use of the appropriate fi-substituted-coumarin. The compounds of the present invention have anticoagulant activity.

We claim:

1. The products, 3-R, R'-aminomethyl-4-hydroxy-6- X-coumarin, where R is selected from the group consisting of hydrogen and methyl, R is selected from the class consisting of lower alkyl and cycloalkyl groups, R and R together with the N form a heterocyclic group selected from the group consisting of piperidino and morpholino groups, and X is selected from the class consisting of chlorine, bromine, lower alkyl and lower alkoxy groups.

2. The product 3-dimethyl-aminomethyl-4-hydroxy-6- chlorocoumarin.

3. The product 3-cyclohexyl-aminomethyl-4-hydroxy- 6-methoxycoumarin.

4. The product 3-piperidinomethyl-4-hydroxy-6-chlorocoumarin.

5. The product 3-isobutyl-aminomethyl-4-hydroxy-6- bromocoumarin.

6. The product 3-morpholino-methyl-4-hydroxy-6-ethoxycoumarin.

No references cited.

Non-Patent Citations
Reference
1 *None
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3153039 *Nov 19, 1962Oct 13, 1964Hans E KriegerBicyclic aminoketones and method for the production thereof
US3311635 *May 5, 1964Mar 28, 1967Cassella Farbwerke Mainkur AgEthers of 3-alkylamino-4-methyl-7-hydroxy-coumarin
US4845242 *Apr 28, 1987Jul 4, 1989Georgia Tech Research CorporationIsocoumarins with basic substituents as serine proteases inhibitors, anticoagulants and anti-inflammatory agents
US4954519 *Jul 3, 1989Sep 4, 1990Georgia Tech Research CorporationIsocoumarins with basic substituents as serine proteases inhibitors, anticoagulants and anti-inflammatory agents
Classifications
U.S. Classification544/151, 546/197, 549/285
International ClassificationC07D311/54
Cooperative ClassificationC07D311/54
European ClassificationC07D311/54